Inflammatory diseases affect more than fifty million Americans. As a result of basic research in molecular and cellular immunology over the last ten to fifteen years, approaches to diagnosing, treating and preventing these immunity-based diseases has been dramatically altered. Inflammation is a complex protective biological process triggered by irritation, injury or infection, characterized by redness, heat (due to increased blood flow), swelling (due to increased vascular permeability), loss of function and pain (due to sensitization of pain receptors). In addition to the foregoing induced conditions, inflammation can also occur due to age related factors. Additionally, inflammatory response can be undesirably triggered in response to noninfectious agents in individuals having allergies and/or autoimmune diseases. Chronic inflammatory condition and cancer have become emerging health concern in a number of countries across the globe. Inflammation has proven to be part of etiology of several chronic diseases like vasculitis, atherosclerosis, ulcerative colitis, inflammatory bowel syndrome, diabetes, Alzheimer's, Meningitis etc., (Susan Robinson & William Stewart, Inflammatory disease of CNS II: Meningitis and cerebral abscess, ACNR VOLUME 4 NUMBER 4 SEPTEMBER/OCTOBER 2004). Non-steroidal anti-inflammatory drugs are most commonly used remedies for inflammatory diseases. Phytochemicals from certain plants were reported to demonstrate anti-inflammatory properties. Like aspirin many -NSAIDS are presumed to work by blocking cyclooxygenase, lipoxygenase and phospholipase. Presently, there has been a tremendous surge in demand for natural non-steroidal anti-inflammatory drugs (NSAIDs) because of their established safety and efficacy, through decades of usage by various cultures (Liana Fraenkel, Dick R. Wittink, John Concato and Terri Fried, Informed choice and the widespread use of anti-inflammatory drugs, Arthritis & Rheumatism, Vol. 51, No. 2, Apr. 15, 2004, pp 210-214). The inflammatory and carcinogenesis processes are known to be triggered by increased metabolic activity of arachidonic acid.
The Arachidonic acid pathway constitutes one of the main cellular mechanism for mediating inflammation. Arachidonic acid diverges down into two main pathways during this process, one is the cyclooxygenase (COX) pathway and the other is lipoxygenase (LOX) pathway. The COX pathway leads to prostaglandins and thromboxane production, where as the LOX pathway leads to leukotrienes (LTS) and hydroxyl eicosatetetraenoic acid (HETEs). These classes of inflammatory molecules exert profound biological effects, which enhance the development and progression of human cancers such as colon, breast, lung, prostrate and pancreas.
Leukotrienes and 5(S)-HETE are important mediators for inflammatory, allergic and obstructive process. Leukotrienes increase microvascular permeability and are potent chemotactic agents. Inhibition of 5-lipoxygenase indirectly reduces the expression of TNF-α(a cytokine that plays a key role in inflammation). 5-Lipoxygenase is therefore the target enzyme for identifying inhibitors, which have potential to cope with a variety of inflammations and hypersensitivity-based human diseases including asthma, arthritis, bowel diseases such as ulcerative colitis and circulatory disorders such as shock and ischemia.
Similarly prostaglandins are intercellular messengers that are produced in high concentration at the sites of inflammation and are capable of causing vasodilatation, increased vascular permeability and sensitizing pain receptors. The pro-inflammatory prostaglandins (PGE2) are produced by inducible isoform cyclooxygenase-2 (COX-2). The prostaglandins that are important in gastrointestinal and renal function are produced by the constitutively expressed isoform, cyclooxygenase-1 (COX-1). COX-1 is the protective housekeeper isoform and it regulates mucosal cell production of mucous membrane that provides a barrier between the acid and pepsin present in gastric secretions. Non-selective COX inhibitors thus produce serious GI side effects. Scientists around the world are thus investing major efforts in identifying non-steroidal anti-inflammatory drugs that inhibit 5-lipoxygenase and cyclooxygenase-2 enzymes. However COX-2 inhibitors are known to have adverse effects on cardiovascular system. A selective COX-2 inhibitor Vioxx (rofecoxib) was withdrawn from the U.S. and worldwide markets on Sep. 30, 2004 due to safety concerns of an increased risk of cardiovascular events.
Various anti-inflammatory substances have heretofore been used, for example, such as steroids like cortisone, dexamethasone; nonsteroids like anthranilic acid derivatives, salicylates, indomethacin, benzydamine and enzymes like proteases. Because of considerable side effects, however, it has been difficult to use these conventional substances in doses sufficient to produce satisfactory anti-inflammatory activities.
Aphanamixis polystachya Wall & Parker also known as Amoora rohituka (Roxb); Wight & Arn Family: maliaceae, is an evergreen medium sized tree with a dense spreading crown and a straight cylindrical trunk that grow up to 15 m in height and 1.5 to 1.8 m in girth. It is widely distributed in sub Himalayan tract from Gonda (UP) eastwards to Bengal, Sikkim and Assam; west wards to Western ghats and Andaman (Y. R. Chanda, The Wealth of India Raw materials, 1985, Vol-I (A) pp 318-320). Various parts of the plant are used in Indian traditional medicine because of their hepatoprotective, antibacterial, anthelmintic and antirheumatic properties. The bark is acrid, depurative and acts as urinary astringent. (Y. R. Chanda; “The Wealth of India Raw materials”, 1985, Vol-I (A) pp 318-320).
Ayurveda prescribes rohituka exclusively for disorders related to spleen and liver. The ethanolic extract of the stem bark of A. polystachya showed anti-tumor activity, and its metabolites, amooranin and prieurianin were identified as active principle responsible for its anti-tumor activity. Amooranin, the triterpene acid reduced the tumor size of mammary adenocarcinoma in animals induced with o-nitrosomethyl urea. The stem bark prolonged the mean survival time of Daltons lymphoma tumor baring mice. (Rabi T., Gupta R. C., Antitumor and cytotoxic investigation of Amoora rohituka, International Journal of Pharmacognosy, V. 33(4): pp. 359-361, 1995 & Rabi T., Antitumor activity of amooranin from Amoora rohituka stem bark. Current Science, V. 70(1): pp. 80-81, 1996). The bark also possesses mild relaxant, cardiotonic, hepatoprotective and cholerectic activities and exhibits analgesic, immunosuppressive and antidiabetic properties (Gole M. K., Dasgupta S., Sur R. K. and Ghosal J., Hepatoprotective effect of Amoora rohituka, International Journal of Pharmacognosy, V. 35(5): pp. 318-322, 1997).
Phytochemical investigations of the plant A. rohituka have resulted in the isolation and identification of several triterpenoids (Kundu, A. B., Ray, S., Chrtteijee, A., Phytochemistry. V. 24, 2123-45, 1985; Rabi, T., Curr. Sci., V 70, p 80, 1996; Chandrasekhar, S., Chakaraborthy, T., J. Indian. Chem. Soc., 208, 1968; The stem bark also contained myristicin eugenol and phenolic compounds and seed oil contained triglyceride composition (Sengupta A Mazumder, U. K., J. Amm. Oil. Chem. Soc., V. 53, 478-7, 1976).
The roots are reputed in the indigenous system of medicine as a cure for diarrhea and dysentery. The stem extract of Aphanamixis polystachya shows hepatoprotective activities. The bark, fruit and leaves of Aphanamixis polystachya taste bitter and are widely used in folk medicine. The bark is commonly used as astringent and used in the treatment of diseases of the liver and spleen for tumors and abdominal complaints. The powdered bark is also used in the treatment of rheumatism. Various parts of the plant are used in Bengali traditional medicine because of their anticancer, antimicrobial, antiinflammatory and hepatoprotective properties.
However, despite of its pharmacological and nutritional benefits, the 5-lipoxygenase inhibitory benefits of A. polystachya is not known. Therefore, there remains a need in the nutraceutical art for nutraceutical composition that offers the health benefit of A. polystachya plant. Further there is a need for natural extract of the said plant for treating inflammatory diseases.
There is an ample literature pertaining to anti-inflammatory activity of plant extracts are available in the prior art.
U.S. Pat. No. 6,521,268 describes antibacterial and anti-inflammatory compositions with Inula helenium L. extract and water soluble chitosan.
U.S. Pat. No. 6,537,977 describes anti-inflammatory agent and a pharmaceutical composition, which contains glycosaminoglycan having at least one sulfate group or a pharmaceutically acceptable salt along with an immunosuppressant.
U.S. Pat. No. 4,777,174 describe novel analgesic and anti-inflammatory compositions comprising caffeine together with a selected non-narcotic analgesic or non steroidal anti-inflammatory drug or a selected narcotic analgesic, or both.
U.S. Pat. No. 4,473,551 describes a composition and method for the treatment of disorders having an inflammatory component comprising essentially whole cartilage, or a greater than 100,000 molecular weight fraction obtained from an aqueous extract, in combination with glucosamine or a substance affording glucosamine under the conditions of treatment, administered topically or parentally.
U.S. Pat. No. 6,346,278 describes anti-inflammatory, and particularly anti-arthritic, treatment of a human or animal patient comprising administration of an effective amount of a lipid extract of Perna canaliculus or Mytilus edulis to the said subject.
U.S. Pat. No. 4,687,781 describes analgesic and anti-inflammatory compositions, which comprises a therapeutically effective amount of hydrocinnamic acid alone, or in combination with one or more amino acids selected from the group consisting of D-phenylalanine, DL-phenylalanine, D-leucine, and DL-leucine and synergistically effective amount of a second therapeutic agent selected from the group consisting of aspirin or an aspirin-type non-steroidal anti-inflammatory and anti-pyretic agent.
WO03047599A1 provides an anti-inflammatory composition containing iridoid glycoside compound, catalposide isolated from stem bark of Catalpa ovata as an active ingredient for treating inflammatory response by inhibiting inducible nitric oxide synthase iNOS, NF-κB, TNF-alpha, IL-1beta and IL-6.
WO8809654A1 describes depigmentation and anti-inflammatory compositions containing mulberry extract and optionally hydroquinone and kojic acid.
KR4103984A describes anti-inflammatory composition containing the extracts of bojungikgitang or kagam-bojungikgitang as active ingredient which has no adverse side effect on human body. The anti-inflammatory composition is characterized by containing the extract of bojungikgitang which is composed of ginseng, Astragalus membranaceus (FISCH.) BGE, Angelica gigas Nakai, Atractylodes Rhizoma Alba, Citrus Aurantium L. subsp, Nobilis markino, licorice root, Bupleurum falcatum L., and Cimicifyga simplex Worm, or kagam-bojungikgitang which is composed of ginseng, Astragalus membranaceus (FISCH.) BGE, Angelica gigas Nakai, Atractylodes Rhizoma Alba, Citrus Aurantium L. subsp, Nobilis markino, licorice root, Artemisiae iwayomogii Herba and Scutellariae Radix.
Thus none of the prior art mentioned above describes the use of powder or extract derived from Aphanamixis polystachya and its applications, as a 5-lipoxygenase inhibiting agent and there has been no attempt to treat 5-lipoygenase mediated disorders using Aphanamixis polystachya extract.
There exists a need for nutraceutical composition that offers the health benefits of Aphanamixis polystachya. There also exists a need for pharmaceutical composition containing Aphanamixis polystachya. Further there is a need for natural product containing the said extract with other anti inflammatory agents, which inhibit 5-lipoxygenase enzyme.
Therefore the present invention is directed to a novel use of extract or fraction derived from Aphanamixis polystachya to treat 5-lipoxygenase mediated disorders in animals or humans.
It is therefore an object of the present invention to provide a non-toxic dietary supplement composition, which inhibits 5-lipoxygenase enzyme and prevents or cure 5-lipoxygenase mediated disorders, like, but not limited to rheumatoid arthritis, periodontal disease, asthma, bowel disease such as ulcerative colitis, circulatory disorders such as shock and ischemia, free radical mediated disorders such as Alzheimer's, Parkinson's and cardiovascular disease.
Thus the invention is directed to a novel mechanism of action of A polystachya plant extract or fraction, which exhibit 5-lipoxygenase inhibitory activity and a process of extracting or fractionation thereof.